Marker Of Progression Research Articles

Serum biomarkers as prognostic markers for Alzheimer's disease in a clinical setting.

Blood-based glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (pTau) have shown promising prognostic potential in Alzheimer's disease (AD), but their applicability in clinical settings where comorbidities are prevalent remains uncertain. Simoa assays quantified GFAP, NfL, and pTau181 in retrospectively retrieved prediagnostic serum samples from 102 AD patients and 21 non-AD controls. Higher serum GFAP levels predicted earlierclinical presentation and faster subsequent Mini-Mental State Examination decline in AD patients. Serum NfL levels were increased in patients with arterial hypertension (AHT), kidney dysfunction, and a history of stroke and only demonstrated predictive value for time to clinical AD presentation after adjustment for these comorbidities. Serum pTau181 instability during long-term storage at -20°C prevented its prognostic evaluation in retrospectively retrieved serum samples. Serum GFAP is a robust prognostic marker for AD progression, whereas NfL is impacted by various comorbidities, which complicates the interpretation of its prognostic value. Serum GFAP levels predict time to clinical AD presentation.Serum NfL levels are increased by hypertension, kidney disease, and stroke history.Prognostic value of serum NfL in AD is only evident after comorbidity correction.Serum levels of GFAP, but not NfL, increase over time within prediagnostic AD stages.

Vacuolar protein sorting 13 homolog C was associated with motor progression in Parkinson's disease.

The SNP rs2414739 of Vacuolar protein sorting 13 homolog C(VPS13C) gene was identified to be linked with Parkinson's Disease (PD). Explore the clinical progression feature of PD patients with rs2414739 variant. Longitudinal data were obtained from the Parkinson's Progression Marker Initiative (PPMI) cohorts. Linear mixed models were used to test the effects of VPS13C with the progression of PD assessed by different scales. A total of 333 patients with PD were included and divided into rs2414739 carriers (n=138) and noncarriers (n=195). Patients with PD carrying VPS13C mutation had slower progression, assessed by total scores of MDS-UPDRS (II+III) (β=-1.834, p=0.000, 95%CI: -2.767, -0.901) than noncarriers. The effect of VPS13C was significant both in the rate of change of UPDRS-II scores (β=-0.284, p=0.028, 95%CI: -0.537, -0.031) and UPDRS-III scores (β=-0.894, p=0.009, 95%CI: -1.558, -0.228). We further divided VPS13C carriers into heterozygous and homozygous carriers, and found that the rate of change of UPDRS(II+III) (β=-1.165, p=0.039, 95%CI: -2.265,-0.062) scores and UPDRS-III scores (β=-9.521, p=0.041, 95%CI: -18.524,-0.532) were significantly slow in heterozygous VPS13C carriers. There was only 20 homozygous VPS13C carriers, which was too small a sample to perform the analysis. VPS13C was associated with slow motor progression in PD patients.

Detection of Fast Decliner of Diabetic Kidney Disease Using Chiral Amino Acid Profiling: A Pilot Study.

Biomarkers for the prediction of diabetic kidney disease are still unsatisfactory. Although D-amino acids have been shown to reflect kidney conditions, their efficacy in treating diabetic kidney disease (DKD) has not been demonstrated. This study explored the potential role of D-amino acids as progression markers for DKD, an aspect not addressed previously. We performed comprehensive D-amino acid measurements and collected the longitudinal estimated glomerular filtration rate (eGFR) data of 135 patients. We defined fast decliners (FDs) as patients exhibiting > 10% decline from baseline eGFR per year and compared the D-amino acid levels of FDs and non-FDs. Then, we verified that D-amino acids could predict FDs independent of creatinine levels. In patients with diabetic kidney disease, D-serine, D-alanine, and D-proline were only detected in the blood, while 15 D-amino acids were detected in the urine. Using supervised orthogonal partial least squares analysis, blood D-serine and urine D-amino acid levels were identified as features characterizing diabetic kidney disease. Baseline blood D-serine levels and ratios did not differ between the FD and non-FD groups; however, short-term changes in blood D-serine levels differed. This study emphasized the significance of D-serine as a prognostic marker for DKD, an aspect not identified in previous research.

P-1754. An Antimicrobial Stewardship Program (ASP) Without Antibiotic Restrictions - Performance Update

Abstract Background In 2011, University Medical Center of Southern Nevada (UMC) in Las Vegas presented introductory results of a simple, yet effective ASP program with the unique strategy of not restricting antibiotics. Since this time, ASP has continued to strive towards appropriate antimicrobial use in an attempt to improve patient care and minimize development of resistance. This project is an update of the progress of this ASP program in terms of resistance, antibiotic use and costs. Methods ASP started January 2008 with minimal resources. Baseline activities included targeted medication use evaluation (MUE), duration regulation, expansion of infection prevention and education. In contrast to many ASP programs our program did not restrict antibiotics – formulary agents were available for any practitioner. Over time activities were adjusted, reporting technologies advanced although personnel resources remained limited. ASP modifications:Added MUE agentsTiered sensitivity reportingReduce duration to 7 daysExpand service to 6 days per week Deviating from initial procedures, in 2015 we implemented restriction of 5 “last-line” antimicrobials to UMC employed Infectious Disease Physicians (table 1) using the EHR. Markers of ASP progress was monitored by rates of organism isolation per 1000 patient days and antimicrobial in days of therapy per 1000 patient days. Financial implications were based on antibiotic expenditures per adult patient day. Results Monitored bacterial pathogens decreased 65 – 94% (table 2). The largest reduction was with Acinetobacter sp. followed by carbapenem resistant P. aeruginosa. Antibiotic use also improved (table 3). Overall use was decreased 71.3 ± 14.7% with the largest changes with fluoroquinolones and piperacillin/tazobactam. Of note, not all antibiotics reported are MUE, and use of these agents still improved. Despite expanding formulary, and cost monitoring activities, antibiotic expenditures decreased 47% per adult patient day. Conclusion ASP at UMC has demonstrated that simple programs, with limited resources, can decrease the use of unnecessary antimicrobial agents and isolation of specific bacterial pathogens. Additional benefits include a decrease in hospital costs without requiring significant restriction of antimicrobial agents. Disclosures Kimberly D. Leuthner, PharmD, FIDSA, AbbVie Inc.: Advisor/Consultant|AbbVie Inc.: Honoraria|Basilea Pharamceutica: Advisor/Consultant|La Jolla Pharmaceutical Company: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|Shionogi, Inc: Honoraria

Left atrial function and left atrioventricular coupling indices for atrial fibrillation prediction in hypertrophic cardiomyopathy

Abstract Background In hypertrophic cardiomyopathy (HCM), atrial fibrillation (AF) is a marker of disease progression and worse outcome, increasing the risk of thromboembolic events. Identification of HCM patients (pts) at risk of AF is pivotal for their clinical management and follow-up. Purpose We aimed to explore whether a detailed echocardiographic evaluation of the left atrium (LA) remodeling and function in HCM pts might improve the predictive value for new AF compared to standard parameters. Methods In consecutive HCM pts referred to our Cardiomyopathy Clinic between 2020 and 2023, we assess left ventricular (LV) and LA volumes and strain by two-dimensional echocardiography (2DE), and LV and LA volumes and total LA emptying fraction (EF) by three-dimensional (3DE) echocardiography. 3DE left atrioventricular coupling index (LACI) was calculated as the ratio of respective LA to LV end-diastolic volumes and expressed as percentage %. Clinical, ECG, and 48h ECG Holter data were also collected. Results A total of 180 HCM pts (58±18 years, 55% men) were followed for 23±13 months. Twenty-seven patients experienced at least one episode of AF during follow-up. They were older and had more impaired LV global longitudinal strain (GLS) (-13±4% vs -15±4%, p=0.004), total LA EF (31±12 vs 42±11%, p=0.001) and LA reservoir strain (LASr, 10±6 vs 16 ±8%, p=0.001) compared to pts without AF. In addition, larger values of 3DE LACI (75±51% vs 43±25%p=0.009) were found in the HCM pts with new AF episode during follow-up. At Cox univariable analysis, 3DE LACI, LA EF and LASr were associated with AF (AUC 0.68, 0.69 and 0.72, respectively, p<0.001 for all). The optimal cutoffs for predicting AF were > 59% for 3DE LACI and < 26% for LA EF with significant discriminative value in Kaplan-Meier analysis. The addition of 3DE LACI and LA EF to a model including LV GLS and 2DE LA volume had a significant incremental value for predicting the occurrence of AF (Figure 1). Conclusions In HCM patients, the advanced evaluation of LA function and left atrio-ventricular coupling by 3DE may improve the identification of patients at risk for subsequent AF episodes within 1 year follow-up. Predictive Model

Biomarkers associated with progression of infantile hemangioma: Exploratory study.

To identify patients with infantile hemangioma (IH) in need of early-stage treatment in this multicenter, prospective, observational study, we investigated the potential of plasma cytokines as a clinically useful marker. Plasma samples were collected at three time points from 41 patients with infantile hemangioma: baseline (days 14-60 after delivery), visit 1 (days 61-150, the proliferative phase), and visit 2 (days 151-395, the involuting phase). With a twofold or more increase in tumor volume during the baseline-visit 1 period regarded as progression, progression was seen in 15 cases (36.6%). In the first step, cytokine arrays were performed using plasma samples in five progressive and five non-progressive cases. Plasma levels of six cytokines at baseline were selected for a prediction marker of change in tumor volume during baseline-visit 1. Validation enzyme-linked immunosorbent assay indicated that the baseline growth differentiation factor 1 (GDF1) concentration tended to correlate with the proliferation ratio of total lesions or target lesion during baseline-visit 1, although without statistical significance. However, the plasma GDF1 concentrations were significantly lower in patients with a fourfold or more increase in total volume (p = 0.013). Furthermore, changes in plasma interleukin (IL)-7Rα levels showed a statistically significant inverse correlation between volume change of the target lesion during baseline-visit 1 (p = 0.0069). Our results suggest that plasma GDF1 measurement after birth is a useful marker for progression of IH. Additionally, the downregulation of IL-7Rα that begins several months after birth may also contribute to tumor growth. (UMIN-CTR: UMIN000038574).

Dopamine genetic risk scores and psychiatric symptoms: Interacting risk factors for impulse control behaviours in de novo Parkinson's disease.

Up to 45% of patients with Parkinson's disease (PD) experience impulse control disorders (ICDs), characterized by a loss of voluntary control over impulses, drives or temptations. This study aimed to investigate whether previously identified genetic and psychiatric risk factors interact towards the development of ICDs in PD. A total of 278 de novo PD patients (ICD-free at enrollment) were selected from the Parkinson's Progression Markers Initiative database. ICD presence at baseline and yearly follow-up assessments were evaluated via the Questionnaire for Impulsive-Compulsive Disorders. Symptoms of anxiety and depression at baseline were measured via the State-Trait-Anxiety Inventory and Geriatric Depression Scale, respectively. Furthermore, an individual dopamine genetic risk score was calculated according to polymorphisms in genes coding for dopamine (D1, D2 and D3 receptors and catechol-O-methyltransferase), with higher scores reflecting higher central dopamine neurotransmission. In total, 146 participants (47.5%) developed an ICD with an average onset time of 36 months (range 3-96) from baseline. Results from a Cox proportional hazards model showed a trait anxiety × genetics interaction, suggesting that individuals with both higher baseline trait anxiety scores and higher dopamine genetic risk scores were at increased risk of ICD development. This interaction remained significant after controlling for age, sex and motor symptom severity. Our findings suggest that genetic and psychiatric predictors of impulsivity in PD interact and jointly yield increased ICD risk during the course of the disorder. This implies that early screening of anxiety symptoms in combination with genotyping can be useful to identify those at risk for ICD.

Transcriptomics profiling of Parkinson’s disease progression subtypes reveals distinctive patterns of gene expression

Background Parkinson’s Disease (PD) varies widely among individuals, and Artificial Intelligence (AI) has recently helped to identify three disease progression subtypes. While their clinical features are already known, their gene expression profiles remain unexplored. Objectives The objectives of this study were (1) to describe the transcriptomics characteristics of three PD progression subtypes identified by AI, and (2) to evaluate if gene expression data can be used to predict disease subtype at baseline. Design This is a retrospective longitudinal cohort study utilizing the Parkinson’s Progression Markers Initiative (PPMI) database. Methods Whole blood RNA-Sequencing data underwent differential gene expression analysis, followed by multiple pathway analyses. A Machine Learning (ML) classifier, namely XGBoost, was trained using data from multiple modalities, including gene expression values. Results Our study identified differentially expressed genes (DEGs) that were uniquely associated with Parkinson’s disease (PD) progression subtypes. Importantly, these DEGs had not been previously linked to PD. Gene-pathway analysis revealed both distinct and shared characteristics between the subtypes. Notably, two subtypes displayed opposite expression patterns for pathways involved in immune response alterations. In contrast, the third subtype exhibited a more unique profile characterized by increased expression of genes related to detoxification processes. All three subtypes showed a significant modulation of pathways related to the regulation of gene expression, metabolism, and cell signaling. ML revealed that the progression subtype with the worst prognosis can be predicted at baseline with 0.877 AUROC, yet the contribution of gene expression was marginal for the prediction of the subtypes. Conclusion This study provides novel information regarding the transcriptomics profiles of PD progression subtypes, which may foster precision medicine with relevant indications for a finer-grained diagnosis and prognosis.

Warrick score in rheumatoid-arthritis interstitial lung disease: a promising tool for assessing the extent and progression of lung involvement

BackgroundThe clinical manifestations and course of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) exhibits considerable heterogeneity. In this study, we aimed to explore radiographic progression over a defined period, employing the Warrick score as a semi-quantitative measure in early RA-ILD, and to assess the associated risk factors for progression.MethodsRA-ILD patients underwent consecutive Warrick scoring based on initial high-resolution computed tomography (HRCT) at diagnosis and the first follow-up. Associations between Warrick scores, pulmonary function tests, and patient characteristics were analyzed. The ROC curve assessed the predictive performance of the Warrick score change rate for ILD progression, while multivariable logistic regression analysis identified risk factors for progression.ResultsSignificant correlations were found between Warrick scores and age at RA-ILD diagnosis, age at ILD diagnosis, and baseline DAS28-ESR. For the severity score, correlations were r = 0.359, r = 0.372, and r = 0.298 (p = 0.001, p < 0.001, p = 0.014, respectively); for the extent score, r = 0.364, r = 0.318, and r = 0.255 (p = 0.001, p = 0.005, p = 0.038, respectively); and for the total score, r = 0.376, r = 0.367, and r = 0.280 (p < 0.001, p = 0.001, p = 0.022, respectively). Annual changes in severity, extent, and total Warrick scores showed sensitivities of 91–97% and specificities of 98% for predicting progression over a 5-year follow-up. Cut-off values were 0.0278 for the severity score (AUC 0.954), 0.0227 for extent score (AUC 0.976), and 0.0694 for total score (AUC 0.946). Warrick severity, extent, and total scores increased significantly during follow-up. Age > 50 years (OR 7.7; p = 0.028) and baseline usual interstitial pneumonia (UIP) pattern (OR 3.1, p = 0.041) were identified as risk factors for progression.ConclusionsAdvanced age and UIP pattern were significant risk factors for progression. Warrick scoring may may help predict progression in RA-ILD, particularly through changes in severity, extent, and total scores. Due to the retrospective design and small sample size, further prospective studies with larger cohorts are needed to confirm these findings and validate Warrick scoring as a reliable marker for RA-ILD progression.

PSMA-targeted delivery of docetaxel in prostate cancer using small-sized PDA-based micellar nanovectors.

In this study, we present the first comparative analysis of active and passive drug delivery systems for docetaxel (DTX) in prostate cancer using supramolecular self-assembled micellar nanovectors. Specifically, we developed two novel micelles based on polydiacetylenic amphiphiles (PDA) for passive and active targeting. The active targeting micelles were designed with a prostate-specific membrane antigen (PSMA) ligand, ACUPA, to facilitate recognition by PSMA-positive cancer cells. These PDA-based micelles feature a well-defined structure with a hydrophobic PDA core and a surface functionalized with PEG, and for active targeting, ACUPA. Our micelles demonstrated excellent encapsulation capacity, significantly improving DTX solubility in water, a crucial factor for clinical drug use. In vitro studies confirmed the safety and cytotoxic profiles of both systems, with ACUPA-functionalized micelles showing notable internalization into PSMA-positive LNCaP cells, mediated through the PSMA-ACUPA interaction. In vivo imaging revealed preferential accumulation of ACUPA-functionalized nanomicelles in LNCaP xenograft tumors, suggesting enhanced retention via specific ACUPA-PSMA interactions and active uptake by LNCaP cells. Notably, Balb/c-Foxn1nu/nu early in vivo studies showed a marked reduction in tumor volume and tumor expression levels of proliferation, cell cycle progression, cell survival and anti-apoptotic markers with DTX-loaded micelles functionalized with ACUPA compared to those without ACUPA. Overall, our studies collect initial evidence regarding the feasibility of supramolecular self-assembly of ACUPA-PDA-based nanomicelles for PSMA-targeted drug chemotherapy delivery developments.

Baseline liver fibrosis-4 score correlates to the progression of anxiety and cognitive impairment in patients with Parkinson’s disease

BackgroundNon-alcoholic fatty liver disease (NAFLD) or liver fibrosis may share similar pathophysiological features with Parkinson’s disease (PD), yet their correlation was unclear. This study aimed to explore their correlation between PD and liver fibrosis using the fibrosis-4 score (FIB-4) as a surrogate marker.MethodsWe analyzed Parkinson’s Progression Markers Initiative (PPMI) data and enrolled PD patients with comprehensive baseline and 5-year follow-up time-point clinical data. Participants were categorized based on FIB-4 levels to assess the association between FIB-4 scores and various clinical scales, controlling for potential confounders. Differences in the progression of clinical scales over five years were compared using generalized linear mixed models (GLMM).ResultsBaseline FIB-4 levels positively correlated to scores of baseline section III of the Unified-Parkinson Disease Rating Scale (UPDRS III) (r = 0.145, p = 0.017), Epworth Sleepiness Scale (EPSS) (r = 0.140, P = 0.022), Hopkins Verbal Learning Test (HVLT)-delayed recall (r = 0.128, P = 0.036) and HVLT-retention (r = 0.128, p = 0.036). GLMM analysis revealed an independent correlation between FIB-4 subgroup*time and several clinical scales including the State-trait Anxiety Inventory (STAI), Symbol Digit Modalities Test (SDMT), Semantic Fluency Test (SF), HVLT-total recall, and HVLT-delayed recall, with the high FIB-4 subgroup exhibiting a greater decline in these scores compared to the low FIB-4 subgroup (all p&amp;lt;0.05).ConclusionElevated baseline FIB-4 correlated to more severe baseline daytime sleepiness, motor symptoms, and memory function in PD patients, along with a more rapid decline in cognitive functions such as executive function, information processing ability, and memory. Additionally, a high FIB-4 might confer a protective effect against anxiety.

P0073 Evaluation of PYGL as a Biomarker and Therapeutic Target in Ulcerative Colitis

Abstract Background Inflammation begins when innate immune cells recognize and respond to infections or tissue injuries to protect the body. In particular, cells such as macrophages and dendritic cells require more energy to manage these conditions. Glycogen metabolism is a crucial function for cells recruited to the site of inflammation to obtain energy. Within that process, glycogen phosphorylase plays a pivotal role as an enzyme for glycogenolysis. Because ulcerative colitis (UC) is a long-term condition in which the colon and rectum become inflamed, patients with the disease might have high levels of protein or activity of glycogen phosphorylase (PYGL) in the blood. Therefore, this study aims to identify the protein level and activity of PYGL in the serum and peripheral blood mononuclear cells (PBMC) of ulcerative colitis patients. Methods After blood from UC patients was provided by Daejeon St. Mary's Hospital, the PBMCs were isolated using Leucosep tube pre-filled with separation medium (Greiner bio-one, 163288), and the serum was isolated by centrifugation at 1000 x g for 10 minutes in a refrigerated centrifuge (Labogene, 1248R). The PBMCs were stored in an LN2 cell storage tank (ICBiomedical, LS6000), and the serum was stored in a deep freezer (Nihon freezer, CLN-52UW) at -80°C until samples of 60 patients were gathered. To compare with UC patients, normal human PBMCs (STEMCELL Technologies, 70025.1) were used. PYGL levels in serum and PBMCs from normal and UC patients were measured using Human PYGL ELISA Kit (Colorimetric) (Novus, NBP2-82520). PYGL activity in serum and PBMCs from normal and UC patients were measured using Glycogen phosphorylase activity assay kit (Colorimetric) (Abcam, ab273271). Activity Vmax and level from serum and PBMCs were analyzed using an unpaired t-test to determine significant differences (p &amp;lt; 0.05), fitting the standard. Activity reaction curve from serum and PBMCs was anlyzed using an mutiple unpaired t-test to determine significant differences (q &amp;lt; 0.05). GraphPad Prism 10 software was used for all analysis and the data were presented as Mean and SEM. Results Significant differences in PYGL activity were observed between UC patients and healthy controls in both serum and PBMC samples, though PYGL levels did not exhibit notable variation. These findings support the hypothesis that PYGL activity is linked to UC pathology and may serve as a marker for disease severity and progression. Conclusion This study provides initial evidence that PYGL activity could be a predictive biomarker and therapeutic target in UC. Future studies are warranted to further elucidate its role and assess the potential of PYGL inhibitors as a treatment strategy for autoimmune and inflammatory conditions like UC. References Ji Q, Li H, Cai Z, Yuan X et al. Share PYGL-mediated glucose metabolism reprogramming promotes EMT phenotype and metastasis of pancreatic cancer. Int J Biol Sci. 2023 Mar 21;19(6):1894-1909. Ma J, Wei K, Liu J et al. Glycogen metabolism regulates macrophage-mediated acute inflammatory responses. Nat Commun. 2020 Apr 14;11(1):1769. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS. Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012 Feb 1;441(3):763-87. Thwe PM, Pelgrom LR, Cooper R et al. Cell-Intrinsic Glycogen Metabolism Supports Early Glycolytic Reprogramming Required for Dendritic Cell Immune Responses. Cell Metab. 2019 Jul 2;30(1):225.

Baseline PSMA PET/CT parameters predict overall survival and treatment response in metastatic castration-resistant prostate cancer patients.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with varying survival outcomes. This study investigated whether baseline PSMA PET/CT parameters are associated with survival and treatment response. Sixty mCRPC patients underwent [18F]PSMA-1007 PET/CT before treatment with androgen receptor-targeted agents (ARTAs) or chemotherapy. Intensity-based parameters, volumetric parameters, metastatic sites and DmaxVox (distance between the two outermost voxels) from baseline PSMA PET/CT were collected, as well as age, Gleason score and laboratory parameters. Cox regression analysis evaluated their prognostic value for overall survival (OS). Additionally, a preliminary lesion-level analysis was done (n = 241 lesions) with lesion location and twelve radiomic features selected from previous literature. Logistic regression evaluated their association with PSMA PET/CT-based lesion progression after 3-4 months of treatment. Total tumour volume (PSMA-TV) (HR = 1.41 per doubling [1.17-1.70]), total lesion uptake (TL-PSMA) (HR = 1.40 per doubling [1.16-1.69]) and DmaxVox (HR = 1.31 per 10 cm increase [1.07-1.62]) were prognostic for OS, each independent of baseline PSA level (HR = 0.82 per doubling [0.68-0.98]), haemoglobin level (HR = 0.68 per mmol/L increase [0.49-0.95]) and line of treatment. On lesion-level, location (prostate vs bone OR = 0.23 [0.06-0.83]) and SUVmean (OR = 1.72 per doubling [1.08-2.75]) were independent prognostic markers for lesion progression, morphological and texture-based radiomic features were not. Baseline PSMA PET/CT scans have prognostic value in mCRPC patients and can potentially aid in treatment decision-making. DmaxVox can serve as a simpler alternative to PSMA-TV when automated segmentation software is not available. When combined with PSMA-TV, lower PSA levels indicated worse OS, which may be a marker of tumour dedifferentiation. Further research is needed to validate these models in larger patient cohorts. Question mCRPC is a highly heterogeneous disease, requiring good prognostic markers. Findings PSMA-TV was the best independent prognostic marker for OS; maximum distance between lesions (DmaxVox) can be used as a simpler alternative. Clinical relevance Baseline PSMA PET/CT parameters representing tumour burden were independently associated with OS in mCRPC patients, providing prognosticinsights for clinical decision-making. Although PSMA-TV was the best prognostic marker, DmaxVox can serve as an easier to obtain alternative.

Identification of pain-related long non-coding RNAs for pulpitis prediction.

We investigated the recently generated RNA-sequencing dataset of pulpitis to identify the potential pain-related lncRNAs for pulpitis prediction. Differential analysis was performed on the gene expression profile between normal and pulpitis samples to obtain pulpitis-related genes. The co-expressed gene modules were identified by weighted gene coexpression network analysis (WGCNA). Then the hypergeometric test was utilized to screen pain-related core modules. The functional enrichment analysis was performed on the up- and down-regulated genes in the core module of pulpitis pain to explore the underlying mechanisms. A pain-related lncRNA-based classification model was constructed using LASSO. Consensus clustering and gene set variation analysis (GSVA) on the infiltrating immunocytes was used for pulpitis subtyping. miRanda predicts miRNA-target relationship, which was filtered by expression correlation. Hallmark pathway and enrichment analysis was performed to investigate the candidate target pathways of the lncRNAs. A total of 1830 differential RNAs were identified in pulpitis. WGCNA explored seven co-expressed modules, among which the turquoise module is pain-related with hypergeometric test. The up-regulated genes were significantly enriched in immune response related pathways. Down-regulated genes were significantly enriched in differentiation pathways. Eight lncRNAs in the pain-related module were related to inflammation. Among them, MIR181A2HG was downregulated while other seven lncRNAs were upregulated in pulpitis. The LASSO classification model revealed that MIR181A2HG and LINC00426 achieved outstanding predictive performances with perfect ROC-AUC score (AUC = 1). We differentiated the pulpitis samples into two progression subtypes and MIR181A2HG is a progressive marker for pulpitis. The miRNA-mRNA-lncRNA regulatory network of pulpitis pain was constructed, with GATA3 as a key transcription factor. NF-kappa B signaling pathway is a candidate pathway impacted by these lncRNAs. PCED1B-AS1, MIAT, MIR181A2HG, LINC00926, LINC00861, LINC00528, LINC00426 and ITGB2-AS1 may be potential markers of pulpitis pain. A two-lncRNA signature of LINC00426 and MIR181A2HG can accurately predict pulpitis, which could facilitate the molecular diagnosis of pulpitis. GATA3 might regulate these lncRNAs and downstream NF-kappa B signaling pathway. This study identified potential pain-related lncRNAs with underlying molecular mechanism analysis for the prediction of pulpitis. The classification model based on lncRNAs will facilitate the early diagnosis of pulpitis.

Predictive value of enhanced corneal biomechanical parameters for ectasia progression.

To determine whether corneal biomechanical parameters can predict ectasia progression. Retrospective observational study. The baseline corneal biomechanical parameters of 64 eyes of 41 young patients (age, < 25 years at the first visit) who were diagnosed with keratoconus (KC) or suspected KC at Osaka University Hospital and followed up for more than two years were reviewed. Suspected KC was defined as borderline cases with no definitive clinical or topographical abnormalities in both eyes. The eyes were divided into progressed (P) and non-progressed (NP) groups using the ABCD grading system of Scheimpflug-based tomography. The Scheimpflug-based corneal biomechanical parameters evaluated included deformation amplitude ratio within 2mm, integrated radius, Ambrósio relational thickness to the horizontal profile, stiffness parameter at the first applanation, stress-strain index, E-staging, and Corvis Biomechanical Index. The optimized tomographic/biomechanical index (TBIv2), Belin/Ambrósio Enhanced Ectasia Deviation (BAD-D), and inferior-superior axial steepening values from Scheimpflug-based tomography were also evaluated. Twenty-three and 41 eyes were categorized into the P and NP groups, respectively. Logistic regression analysis showed that age, BAD-D, and TBIv2 could predict ectasia progression. The specificity, sensitivity, and area under the receiver operating characteristic curve (AUROC) values for BAD-D combined with age were 0.82, 0.60, and 0.83, respectively, whereas those for TBIv2 combined with age were 0.65, 0.82, and 0.82, respectively. Baseline TBIv2 is a potentially useful predictive marker for ectasia progression in young patients, whereas baseline BAD-D could be used for establishing a definitive diagnosis.

Chlorpyrifos induces lung metastases and modulation of cancer stem cell markers in triple negative breast cancer model.

Breast cancer is a major public health problem, and distant metastases are the main cause of morbidity and mortality. Chlorpyrifos is an organophosphate that promotes Epithelial-Mesenchymal Transition-like phenotype in breast cancer cell lines and modulates the Breast Cancer Stem Cells activating two key processes related to the metastatic cascade. Here, we investigated whether Chlorpyrifos may induce distant metastases in an in vivo triple negative tumor model. Also, we studied the expression of Breast Cancer Stem Cell and Epithelial-Mesenchymal Transition activation-markers in Triple Negative Breast Cancer mice tumors and human cells. We demonstrate that Chlorpyrifos modulates stem cell plasticity as a function of growth conditions in monolayer or three-dimensional culture. Furthermore, Chlorpyrifos decreased the doubling period, increased tumor volume, stimulated the infiltration of adjacent muscle fibers and induced lung and lymphatic node metastases in mice. Finally, Chlorpyrifos modulated the expression of Epithelial-Mesenchymal Transition and Breast Cancer Stem Cell markers in mice exposed to the pesticide. All our findings confirm that Chlorpyrifos promotes breast cancer progression, enhances stemness and Epithelial-Mesenchymal Transition marker expression and generates lung metastases in an in vivo model induced in mice.

Mutant GNAS drives a pyloric metaplasia with tumor suppressive glycans in intraductal papillary mucinous neoplasia.

Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recent studies have shown that pancreatic precancer is characterized by a transcriptomic program similar to gastric metaplasia. The aims of this study were to assay IPMN for pyloric markers, to identify molecular drivers, and to determine a functional role for this program in the pancreas. Pyloric marker expression was evaluated by RNA-seq and multiplex immunostaining in patient samples. Cell lines and organoids expressing KrasG12D +/- GNASR201C underwent RNA sequencing. A PyScenic-based regulon analysis was performed to identify molecular drivers, and candidates were evaluated by RNA-seq, immunostaining, and small interfering RNA knockdown. Glycosylation profiling was performed to identify GNASR201C-driven changes. Glycan abundance was evaluated in patient samples. Pyloric markers were identified in human IPMN. GNASR201C drove expression of this program as well as an indolent phenotype characterized by distinct glycosyltransferase changes. Glycan profiling identified an increase in LacdiNAcs and loss of pro-tumorigenic Lewis antigens. Knockdown of transcription factors Spdef or Creb3l1 or chitinase treatment reduced LacdiNAc deposition and reversed the indolent phenotype. LacdiNAc and 3-sulfoLeA/C abundance discriminated low from high grade patient IPMN. GNASR201C drives an indolent phenotype in IPMN by amplifying a differentiated, pyloric phenotype through SPDEF/CREB3L1 which is characterized by distinct glycans. Acting as a glycan rheostat, mutant GNAS elevates LacdiNAcs at the expense of pro-tumorigenic acidic Lewis epitopes, inhibiting cancer cell invasion and disease progression. LacdiNAc and 3-Sulfo-LeA/C are mutually exclusive and may serve as markers of disease progression.

Characterization of NK Cells Using Single-Cell RNA Sequencing in Patients With Acute-On-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is characterized by fast progression and high mortality, with systemic inflammation and immune paralysis as its key events. While natural killer (NK) cells are key innate immune cells, their unique function and subpopulation heterogeneity in ACLF have not been fully elucidated. This study aimed to investigate the characteristics of NK cell subsets in the peripheral blood of patients with ACLF and determine their roles in the inflammatory responses. Circulating NK cells (14 751 cells) from patients with ACLF and healthy controls (HCs) were subjected to single-cell RNA sequencing (scRNA-seq). Clustering and annotation were used to identify the features of NK cell subsets and the characteristics of disease progression in ACLF. Four NK cell subsets were obtained, including adaptive NK cells, mature NK cells, inflamed NK cells, and CD56bright NK cells. Compared with the HCs, the patients with ACLF had a significantly lower proportion of Mature NK cells and a higher proportion of Inflamed NK cells. Quasi-temporal analysis showed that Inflamed NK cells were highly enriched in the late quasi-temporal sequence, and genes related to pro-inflammatory were significantly up-regulated in Inflamed NK cells. In addition, scRNA-seq and flow cytometry confirmed that the expression level of cell migration inducing hyaluronidase 2 (CEMIP2) in NK cells progressively increased from the HC group to the ACLF survival group and then to the ACLF death group. scRNA-seq reveals that Inflamed NK cell subsets are associated with ACLF progression and poor prognosis. CEMIP2 may be a molecular marker for ACLF progression.

Association of Favorable Cerebrospinal Fluid Markers With Reversion of Mild Cognitive Impairment Due to Parkinson's Disease.

Cognitive impairment is a common nonmotor symptom among individuals with Parkinson's disease (PD). Although cognitive impairment generally develops progressively, individuals with PD-associated mild cognitive impairment (PD-MCI) may revert to being cognitively normal (CN), which is referred to as PD-MCI reversion. Previous studies are inconsistent in whether PD-MCI reverters are at greater risk for PD-MCI recurrence relative to CN individuals. Even less is known about how PD-MCI reverters compare with CN individuals or PD-MCI nonreverters in terms of neurodegenerative biomarkers. The authors examined group differences (CN, PD-MCI reversion, and PD-MCI nonreversion) in cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD), including amyloid beta, tau (total [t-tau] and phosphorylated [p-tau]), and alpha-synuclein. Data from the longitudinal international multisite Parkinson Progression Marker Initiative were used. Participants were newly diagnosed as having PD (N=430) and completed a battery of neurocognitive assessments at baseline and annual follow-ups for up to 5 years. Participants were classified as CN, PD-MCI reverters, or PD-MCI nonreverters on the basis of the first two neurocognitive assessments. The PD-MCI nonreversion group had greater p-tau:amyloid beta and t-tau:amyloid beta ratios relative to the PD-MCI reversion group. The CN and PD-MCI reversion groups did not significantly differ in any of the CSF markers. PD-MCI reverters may have a more favorable trajectory in terms of AD pathology relative to PD-MCI nonreverters. Future studies are needed to verify whether PD-MCI reversion may represent an intermediate prognostic group between CN individuals and those with MCI nonreversion.

Clinical impact of PTEN rs701848 as a predictive marker for breast cancer.

The incidence of Breast cancer (BC) is currently augmented and it has become the most common malignant cancer in females. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene as a result of blocking the phosphorylation of PIP3 in PI3K pathway. The computational bioinformatics tools were performed to determine the link between PTEN rs701848T/C genetic variants and breast cancer progression. 50 healthy matched controls and 100 Egyptian women with breast cancer were enrolled in the study. The PTEN rs701848T/C polymorphism was assessed using qRT-PCR. Then the proteomic level of PTEN was measured by ELISA technique. Breast cancer patients had considerably higher (TC) genotype frequency than controls, p = 0.03. Moreover, TC carriers had a higher chance of developing tumors with advanced stage, big tumor size, and metastasis at further sites. Regarding proteomic level of PTEN, a remarkable decline was correlated significantly with disease progression. Moreover, the ROC curve analysis showed that the PTEN protein showed comparable diagnostic accuracy in distinguishing between different BC stages. The current research provides insight into the impact of PTEN as a predictive marker for BC development and progression at genomic and proteomic levels.